The present disclosure relates generally to methods of modulating the multimeric structure of an E6AP ligase protein. In particular, the disclosure relates to the use of small molecule non-competitive inhibitors to disrupt E6AP ligase oligomerization, reducing E6AP ligase activity, or the use of peptide agents that induce oligomerization of E6AP monomers. The disclosure further relates to use of such modulating agents as therapeutic agents for modulating E6AP-related pathologies.